Glucagon receptor is required for long-term survival: a natural history study of the Mahvash disease in a murine model.

Background And Aim: We have described a novel Mahvash disease of hyperglucagonemia and pancreatic neuroendocrine tumors (PNETs) associated with an inactivating glucagon receptor mutation, and identified the glucagon receptor-deficient (Gcgr(-/-)) mice as its murine model. We aim to elucidate the natural history of the rare Mahvash disease by long-term observation of the Gcgr(-/-) mice.

Materials And Method: Wild type (WT) (n=52), heterozygous (n=127), and Gcgr(-/-) (n=56) mice living under standard vivarium conditions were observed without specific treatments over 22 months. Autopsy was performed on dead animals.

Results: The WT and heterozygous mice did not exhibit any measurable differences. The Gcgr(-/-) mice became progressively lethargic and cachexic after 12 months. Random glucose levels were stable in WT and heterozygous mice but decreased with age in the Gcgr(-/-) mice. At the end of observation, 28/56 Gcgr(-/-), 7/52 WT, and 24/127 heterozygous mice died. The survival curve of Gcgr(-/-) mice began to separate from those of WT and heterozygous mice at 12 months and the survival difference widened with age. At 18 months, survival probability was 17% for Gcgr(-/-) mice but 77% for WT and 81% for heterozygous mice. Autopsy revealed numerous PNETs up to 15 mm in diameter in most well-preserved Gcgr(-/-) pancreata (17/20) but none in WT or heterozygous ones. Four Gcgr(-/-) mice developed liver or subcutaneous metastasis.

Conclusion: The untreated Mahvash disease may cause cachexia, severe hypoglycemia, and early death. Patients with Mahvash disease need to undergo life-long surveillance for PNETs. Functional glucagon receptor is thus required for long-term survival.